Injected Eye, Fellow Eye and Systemic Pharmacokinetic Modeling of Intravitreally Administered Bevacizumab

Simulation of retinal drug concentrations after intravitreal administration is still challenging, due to knowledge gaps in ocular physiology such as the molecule-dependent permeability of ocular segments and the mechanisms determining a drugs' diffusion through the vitreous. Current models consider the eye as an isolated organ, however, especially if we are striving for predictions that rely on only plasma data, it is crucial to understand the blood-ocular barrier to draw conclusions for drug exposure in the eye. The aim of this study was (1) to examine large molecule disposition within the rabbit injected eye as well as in the systemic circulation and the uninjected fellow eye using bevacizumab as a tool compound, (2) to show gaps in the current understanding of physiological processes governing drug distribution in the eye and (3) to identify model parameters relevant for eye-plasma drug exchange. We developed a semimechanistic ocular compartmental model to describe large molecule disposition in injected eye, plasma and fellow eye, following intravitreal bevacizumab administration in rabbit, based on literature data. Observations in the fellow eye add additional value to the developed model as they provide valuable new information about the blood-ocular barrier. Starting with a base model building on literature assumptions, we refined the structural model and parameter estimates (e.g., by adjusting the retinal volume) to better describe the observed data in the fellow eye. The simulated concentration-time profiles from our refined model adequately described observed concentrations in the injected eye, plasma and fellow eye. The retinal volume fraction accessible for bevacizumab was estimated at 41% and the retinal pigment epithelium permeability at 5.9 · 10^-9 cm·s^-1, which is in close agreement with the values obtained from in vitro experiments. The introduction of a backflow from the plasma compartment to the aqueous chamber (0.024 mL·day^-1) yielded improved predicted aqueous concentrations in the fellow eye. The developed model increases our knowledge of ocular drug pharmacokinetics within a systemic context, with a more physiological representation of the retinal compartment and new insights into the processes involved at the blood-ocular barrier.